The regulated migration of leukocytes from the blood stream into tissues is a critical component of immune responses as well as immune surveillance. The recognition that T helper cells can be categorized according to their cytokine production phenotype as well as cell surface molecules has provided a framework for investigating immune mediated lung injury with implications for immune surveillance. Th1 cells (producing of IFN-gamma, IL2, and TNF-alpha) have been implicated in a variety of lung disorders including autoimmune and alloimmune lung disease, sarcoid, and hypersensitivity pneumonitis. However, the mechanisms whereby these cells initiate and amplify lung inflammation in vivo remains to be established. In this project, we will use a novel murine model in which an immune reaction initiated by cloned alloreactive T lymphocytes of Th1 phenotype culminates in a remarkably selective lung inflammatory response including vasculitis, alveolitis, and interstitial inflammation. This model has provided an important means for bridging the gap between in vitro observations and in vivo mechanisms of immune lung injury. The focus of our proposed investigations will be on the physiologic role of adhesion molecules and chemokines that specify Th1 cell trafficking to lung. Our specific aims are: (1) to characterize selectin dependent adhesion mechanisms by which Th1 cells initially traffic to lung; and (2) to identify the role of CXCR3 chemokines in sustaining Th1 cell induced lung inflammation. Our work in progress leads us to postulate that Th1 cells selectively adhere in lung by a constitutively expressed receptor on Th1 cells distinct from PSGL-1 that binds to P- and/or E-selectin in lung endothelium. We further hypothesize that activation of Th1 cells which are localized within lung results in release of critical pro-inflammatory cytokines that perpetuate lung-specific inflammation, determined in part by upregulation of host-derived signals that include IFN-gamma inducible chemokines, such as IP-10 and MIG, which selectively recognize Th1 cells through CXCR3 on Th1 cells. The regulation of these "downstream" events may have important consequences in terms of a sustained inflammatory response. Understanding what controls these events is crucial to defining effective strategies for modifying these fundamental biologic responses in patients.